The determination of an individual's physiological status is frequently assisted by chemical analysis for the existence and/or concentration level of an analyte in a body fluid. This practice is common in the diagnosis of diabetes and in the management of this disease. Blood sugar levels can generally fluctuate with the time of day and with the period since the individual's last consumption of food. Management of diabetes often, thus, requires the frequent sampling and analysis of the diabetic's blood for determination of its relative glucose level. The management of this disease by the diabetic will typically involve the sampling of his/her own blood, the self-analysis of the sample for its relative glucose content and the administration of insulin, or the ingestion of sugar, depending upon the indicated glucose level.
Presently, the only approved method for home monitoring of blood chemistry requires drawing blood by using a lance, usually by sticking a finger, and placing a drop of blood on a chemical strip. The resulting chemical reaction causes a change in the color of the strip with that change being read by a desk-top reflectance meter to provide an indication of blood sugar level. Another method also requires drawing blood, placing a drop of blood on a disposable printed circuit (PC) board, and measuring the electrical response of the blood to detect blood sugar level. Some attempts to use infrared techniques to look through the skin to make blood sugar determinations have proven to be less reliable and too expensive for commercial application.
Diabetics who need to control their insulin level via diet or insulin injection may test themselves several times per day, i.e., five or six times per day, the frequency recommended by the American Diabetes Association. Some may choose to test less often than recommended to avoid the unpleasantness associated with drawing blood. Unfortunately, the current methods of monitoring blood glucose levels has many drawbacks. The current methods generally rely upon finger lancing to monitor blood glucose levels, which is not easy for anyone, especially young children and the elderly. Moreover, because blood is involved, there is always the risk of infection and of transmission of blood borne diseases, such as AIDS. Still further, special procedures and systems for handling and disposing of the blood are required. If the blood glucose concentrations in such individuals are not properly maintained, the individuals become susceptible to numerous physiological problems, such as blindness, circulatory disorders, coronary artery disease, and renal failure. For these reasons, there is a great unmet need for a noninvasive method for monitoring blood glucose levels. A substantial improvement in the quality of life of persons suffering from various maladies, such as diabetes mellitus, could be attained if the concentrations of species in body fluids are noninvasively determined. There is accordingly a considerable amount of interest in the development of procedures for making blood sugar level determinations that avoid any need for inflicting injury to the patient.
There are a number of devices on the market to assist the diabetic in the self-testing of the blood sugar level. One such device, developed by Audiobionics (now Garid, Inc.) and described in U.S. Pat. No. 4,627,445, issued Dec. 9, 1986, involves the use of a fixture containing a multi-layered element for the collection of the whole blood sample, the transport of the sample from the point of application on the element to a porous membrane, and the analysis of the blood sample for its glucose contents by a dry chemistry reagent system which is present within the porous membrane.
Other such devices described in U.S. Pat. Nos. 5,462,064 and 5,443,080 and issued to J. P. D'Angelo et al. involve the use of a multi-part system to collect and analyze constituents of body fluid. In D'Angelo et al., the systems rely upon, among other things, a multilayered gel matrix which includes a separate activation gel layer and a separate collection gel layer disposed below the activation gel layer, an osmotic flow enhancer, such as ethyl ether, to facilitate the collection of an analyte fluid, and a chemistry detection methodology to aid in the visual or electronic determination of an analyte under investigation. Ethyl ether, however, is a known skin irritant which is flammable and explosive.
Another such device described in U.S. Pat. No. 5,203,327 and issued to D. W. Schoendorfer et al., involves a method and apparatus for the non-invasive determination of one or more preselected analytes in perspiration. In D. W. Schoendorfer, et al., the fluid is collected in a dermal concentration patch and concentrated by driving off a portion of the substantial water fraction under the influence of body heat, and the analyte is optimally complexed with an immobilized specific binding partner and an indicium of the presence of the analyte is usually experienced.
Other such devices are described in U.S. Pat. Nos. 4,960,467; 4,909,256; 4,821,733; 4,819,645; and 4,706,676 and issued to Peck. According to these patents, the Peck devices involve a dermal substance collection device (DSCD) which provides for the non-invasive, instantaneous and continuous monitoring of chemical substances which are present in detectable amounts in either or both interstitial fluid or sweat or which are on or in the skin. More particularly, the Peck transdermal substance collection devices are comprised of three essential components: (1) a substance binding reservoir, wettable by (2) a liquid transfer medium which allows for liquid bridge transfer of a soluble substance from the skin surface to the biding reservoir by virtue of its wettability by the liquid, and (3) an occlusive cover.
Exemplary of other systems have been previously proposed to monitor glucose in blood, as is necessary, for example, to control diabetic patients. This is represented, for example, by Kaiser, U.S. Pat. No. 4,169,676, Muller, U.S. Pat. No. 4,427,889, and Dahne et al. al., European Patent Publication No. 0 160 768, and Bauer et al., Analytica Chimica Acta 197 (1987) pp. 295-301.
In Kaiser, glucose in blood is determined by irradiating a sample of the blood with a carbon dioxide laser source emitting a coherent beam, at a single frequency, in the mid-infrared region. An infrared beam derived from the laser source is coupled to the sample by way of an attenuated total reflectance crystal for the purpose of contacting the blood sample. The apparatus uses double beam instrumentation to examine the difference in absorption at the single frequency in the presence and absence of a sample.
Muller discloses a system for quantifying glucose in blood by irradiating a sample of the blood with energy in a single beam from a laser operating at two frequencies in the mid-infrared region. The infrared radiation is either transmitted directly to the sample or by way of an attenuated total reflectance crystal for in vitro sampling. One frequency that irradiates the sample is in the 10.53-10.6 micrometer range, while the other irradiating frequency is in the 9.13-9.17 micrometer range. The radiation at the first frequency establishes a baseline absorption by the sample, while glucose absorption by the sample is determined from the intensity reduction caused by the sample at the second wavelength. The absorption ratio by the sample at the first and second frequencies quantifies the glucose of the sample.
Dahne et al. employ near-infrared spectroscopy for non-invasively transmitting optical energy in the near infrared spectrum through a finger or earlobe of a subject. Also discussed is the use of near-infrared energy diffusely reflected from deep within the tissue. Responses are derived at two different wavelengths to quantify glucose in the subject. One of the wavelengths is used to determine background absorption, while the other wavelength is used to determine glucose absorption. The ratio of the derived intensity at the two different wavelengths determines the quantity of glucose in the analyte biological fluid sample.
Bauer et al. disclose monitoring glucose through the use of Fourier-transform infrared spectrometry wherein several absorbance versus wavelength curves are illustrated. A glucose concentration versus absorbance calibration curve, is constructed from several samples having known concentrations, in response to the intensity of the infrared energy absorbed by the samples at one wavelength, indicated as preferably 1035 cm−1.
Notwithstanding the above, the most frequently employed systems for determining the concentration of molecular substances in biological fluids have used enzymatic, chemical and/or immunological methods. However, these techniques generally require invasive methods to draw a blood sample from a subject; typically, blood must be drawn several times a day by a finger prick, such as presently employed by a diabetic and externally determining the glucose level, generally by chemical reaction followed by calorimetric comparative testing. For example, in the determination of glucose by diabetics, such invasive techniques must be performed using present technology.
Because the prior art invasive techniques are painful, individuals frequently avoid having blood glucose measured. For diabetics, the failure to measure blood glucose on a prescribed basis can be very dangerous. Also, the invasive techniques, which rely upon lancing blood vessels, create an enhanced risk for disease transmission and infection.
Thus, there remains a need in many diverse applications for a system for the noninvasive, painless determination of a preselected analyte in a body fluid, such as interstitial fluid, which can be utilized to detect the presence of the preselected analyte. Clearly, in the case of diabetics, it would be highly desirable to provide a less invasive system for analyzing glucose concentrations in the control of diabetes mellitus. However, with respect to transdermal detection mechanism, the extracted analytes which are indicative of widely varying blood sugar levels may produce only very slight changes in developed color shade. In many instances, the difference between developed color shade for an acceptable and an unacceptable blood sugar level cannot be accurately and repeatably detected by the naked eye. To obtain the non-invasive benefits of transdermal glucose measurement technology while ensuring measurement accuracy in what may comprise a life critical testing procedure, it is therefore imperative that the fallible human activity of color shade evaluation and comparison be eliminated from the testing and measurement process.
There is accordingly a need for an ultra-sensitive meter capable of accurately resolving the full range of developed subtle color shade changes produced as a result of transdermal patch extraction and processing of certain analytes of interest. Preferably, the meter should be small, lightweight and portable (hand held). Beyond the obvious requirements for improved sensitivity to subtle differences in color shade, this meter should account for the effects of portability which are adverse to reading accuracy such as background light changes, temperature changes, and unsteady hand-held operation (for example, due to device pressure variation, rotation, and movement), and which are not normally associated with the desk-top meters that are widely employed for measuring blood sugar levels on test strips. Moreover, the entire system for noninvasive detection should be low-cost and suitable for convenient use by non-medical personnel.